Thuan T. Nguyen

Stimulation of muscle protein synthesis by long-term insulin infusion in severely burned patients

ObjectiveTo determine if long-term (7 days) infusion of insulin can ameliorate altered protein kinetics in skeletal muscle of severely burned patients and to investigate the hypothesis that changes in protein kinetics during insulin infusion are associated with an increased rate of transmembrane amino acid transport from plasma into the intracellular free amino acid pool. Summary Background DataIn critically ill patients, vigorous nutritional support alone may often fail to entirely curtail muscle catabolism; insulin stimulates muscle protein synthesis in normal volunteers. MethodsNine patients with severe burns were studied once during enteral feeding alone (control period), and once after 7 days of high-dose insulin. The order of treatment with insulin was randomized. Data were derived from a model based on a primed-continuous infusion of L-[15N]phenylalanine, sampling of blood from the femoral artery and vein, and biopsies of the vastus lateralis muscle. ResultsNet leg muscle protein balance was significantly (p < 0.05) negative during the control period. Exogenous insulin eliminated this negative balance by stimulating protein synthesis approximately 350% (p < 0.01). This was made possible in part by a sixfold increase in the inward transport of amino acids from blood (p < 0.01). There was also a significant increase in leg muscle protein breakdown. The new rates of synthesis, breakdown, and inward transport during insulin were in balance, such that there was no difference in the intracellular phenylalanine concentration from the control period. The fractional synthetic rate of protein in the wound was also stimulated by insulin by approximately 50%, but the response was variable and did not reach significance. ConclusionsExogenous insulin may be useful in promoting muscle protein synthesis in severely catabolic patients.

Current treatment of severely burned patients

OBJECTIVE The authors provide an update on a multidisciplinary approach to the treatment of severely burned patients. A review of studies and clinical trials from the past to the present include fluid resuscitation, sepsis, immune function, hypermetabolism, early excision, wound healing, scar formation, and inhalation injury. SUMMARY BACKGROUND DATA Advances in treating initial burn shock, infection control, early wound closure, and modulation of the hypermetabolic response have decreased morbidity and mortality in the last two decades. Specialized burn care centers, using a multidisciplinary approach, not only successfully treat large burns and their complications, but provide the necessary rehabilitation and psychological support required for readjustment back into society. CONCLUSIONS Thermal injury results in a number of physiologic alterations that can be minimized by adequate fluid resuscitation to maintain tissue perfusion, early excision of burn wounds, and rapid wound coverage. These measures, in combination with antibiotic coverage and nutritional support in the form of early enteral tube feedings, will decrease the hypermetabolic response and the incidence of sepsis that can lead to hemodynamic instability and organ failure. Ongoing clinical trials using anabolic agents (e.g., recombinant human growth hormone) and pharmacologic agents that modulate inflammatory and endocrine mediators (e.g., ibuprofen and propranolol) show promise in the treatment of severe burn injuries.

Effects of insulin on wound healing.

BACKGROUND Insulin plus glucose, given for 7 days to hypermetabolic burn patients, has been shown to stimulate limb protein anabolism. We hypothesized that insulin plus glucose given to burn patients would also stimulate wound healing. METHODS Six patients with burns >40% total body surface area were randomized to receive insulin or placebo in a crossover study during the healing of their first and second donor sites. Insulin treatment was titrated at 25 to 49 U/h to achieve a plasma insulin level of 400 to 900 microU/mL for 7 days. Patients receiving insulin received dextrose 50 at 20 to 50 mL/h, titrated to maintain euglycemia. Donor-site biopsies were taken at 7 days and evaluated by three observers blinded to the treatment. RESULTS The mean (+/-SD) donor-site healing time was reduced from 6.5 +/- 1.0 days with placebo to 4.7 +/- 1.2 days during insulin infusion (p < 0.05). Laminin showed intense staining along the basal lamina and blood vessels. Collagen type IV staining also increased after insulin therapy compared with placebo. CONCLUSION Data indicate that high doses of insulin and glucose can be safely administered to massively burned patients to improve wound matrix formation.

Characterization of growth hormone enhanced donor site healing in patients with large cutaneous burns

BackgroundHuman growth hormone is an anabolic agent that attenuates injury-induced catabolism and stimulates protein synthesis. Recombinant human growth hormone (rhGH) administered therapeutically to patients with massive burns has been shown to increase the rate of skin graft donor site healing. It has been postulated that growth hormone affects wound healing and tissue repair by stimulating the production of insulin-like growth factor-1 (IGF-1) by the liver to increase circulating IGF-1 concentrations. The mechanism by which it improves wound healing, however, remains in question. The authors hypothesize that rhGH up-regulates IGF-1 receptors and IGF-1 levels both systemically and locally in the wound site to stimulate cell mitosis and increase synthesis of laminin, collagen types IV and VII, and cytokeratin. This hypothesis was tested in nine patients with burns covering >40% of total body surface area. ObjectiveThe authors assessed the efficacy of rhGH in promoting several major building materials in the donor site of patients with massive burns. MethodsTen massively burned patients with full-thickness burns covering more than 40% of total body surface area were participants in a placebo-controlled prospective study to determine the efficacy of 0.2 mg/kg/day rhGH on donor site wound healing and to identify some of the major components involved in wound healing and its integrity. ResultsDonor sites in burn patients receiving rhGH showed an increased coverage by the basal lamina of 26% for placebo to 68% coverage of the dermal-epidermal junction. Insulin-like growth factor-1 receptors and laminin, types IV and VII collagen, and cytokeratin-14 all increased significantly. Healing times of the donor sites were significantly decreased compared with patients receiving placebo. ConclusionResults indicate that growth hormone or its secondary mediators may directly stimulate the cells of the epidermis and dermis during wound healing to produce the structural proteins and other components needed to rebuild the junctional structures.

Free radical activity and loss of plasma antioxidants, vitamin E, and sulfhydryl groups in patients with burns: the 1993 Moyer Award.

This study examines the relationship of burn injury and plasma levels of conjugated dienes, total sulfhydryl groups, and vitamin E in patients with thermal injuries. Plasma neopterin levels were determined as an index of macrophage activity and serine elastase as an index of polymorphonuclear cell activation. Thirteen patients with burns, six survivors and seven nonsurvivors, were studied for the first 4 days, then every other day until postburn day 14. Twelve healthy volunteers served as the control group. Survivors had 56% +/- 4% total body surface area burned, and nonsurvivors had 63.9% +/- % total body surface area burned. The patients with burns, compared with the control group, showed elevated plasma levels of the lipid peroxidation products conjugated dienes (0.767 +/- 0.045 vs 0.269 +/- 0.013 Abs at 233 nm) and reduced levels of the natural scavengers of free radicals, vitamin E (196.2 +/- 12.6 vs 841.1 +/- 22.7 micrograms/dl) and total sulfhydryl groups (54.0 +/- 0.4 vs 15.8 +/- 1.0 mumol/dl). The total sulfhydryl groups/conjugated dienes ratio fell at a greater rate (9.8% +/- 3.2% vs 3.2% +/- 0.7%/day) in nonsurvivors than in survivors (p < 0.05 by Mann-Whitney). The levels of elastase were slightly elevated in the patients with burns, but there was no difference between survivors and nonsurvivors. Normal neopterin levels are 3 to 10 nm/L; peak levels were 119 +/- 48 nm/L in nonsurvivors and 37.4 +/- 10 nm/L in survivors. Patients with burns demonstrated evidence of increased oxygen free radical activity and activation of polymorphonuclear cell and macrophages. Nonsurvivors demonstrated increased consumption of antioxidants compared with survivors.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin therapy in burn patients does not contribute to hepatic triglyceride production.

Lipid kinetics were studied in six severely burned patients who were treated with a high dose of exogenous insulin plus glucose to promote protein metabolism. The patients were 20+/-2-yr-old (SD) with 63+/-8% total body surface area burned. They were studied in a randomized order (a) in the fed state on the seventh day of a control period (C) of continuous high-carbohydrate enteral feeding alone, and (b) on the seventh day of enteral feeding plus exogenous insulin (200 pmol/h = 28 U/h) with extra glucose given as needed to avoid hypoglycemia (I+G). Despite a glucose delivery rate approximately 100% in excess of energy requirements, the following lipid parameters were unchanged: (a) total hepatic VLDL triglyceride (TG) secretion rate (0.165+/-0.138 [C] vs. 0.154+/- 0.138 mmol/kg . d-1 [I+G]), (b) plasma TG concentration (1.58+/-0.66 [C] vs. 1. 36+/-0.41 mmol/liter [I+G]), and (c) plasma VLDL TG concentration (0. 68+/-0.79 [C] vs. 0.67+/- 0.63 mmol/liter [I+G]). Instead, the high-carbohydrate delivery in conjunction with insulin therapy increased the proportion of de novo-synthesized palmitate in VLDL TG from 13+/-5% (C) to 34+/-14% (I+G), with a corresponding decreased amount of palmitate from lipolysis. In association with the doubling of the secretion rate of de novo-synthesized fatty acid (FA) in VLDL TG during insulin therapy (P > 0.5), the relative amount of palmitate and stearate increased from 35+/-5 to 44+/-8% and 4+/-1 to 7+/-2%, respectively, in VLDL TG, while the relative concentration of oleate and linoleate decreased from 43+/-5 to 37+/-6% and 8+/-4% to 2+/-2%, respectively. A 15-fold increase in plasma insulin concentration did not change the rate of release of FA into plasma (8.22+/-2.86 [C] vs. 8.72+/-6.68 mmol/kg.d-1 [I+G]. The peripheral release of FA represents a far greater potential for hepatic lipid accumulation in burn patients than the endogenous hepatic fat synthesis, even during excessive carbohydrate intake in conjunction with insulin therapy.

Urea and protein metabolism in burned children: Effect of dietary protein intake

The response of urea metabolic kinetics, the rate of whole-body protein breakdown, and muscle and skin protein synthesis rates to dietary protein intake (1.15 to 2.92 g/kg/d) was assessed in children with 20% to 40% total body surface area burn injury using a primed continuous infusion of 15N2-urea and L-13C6-phenylalanine. Plasma urea concentration, production, and excretion rates increased with dietary protein intake without evidence of approaching maximum plateau values. There was no consistent evidence of urea recycling in these subjects (urea production = excretion) at any level of protein intake. The rate of appearance (Ra) of phenylalanine (an index of whole-body protein breakdown) and rate of muscle protein synthesis were independent of dietary protein, whereas there was a significant increase in skin protein synthesis with higher protein intake. We conclude that there seems to be little benefit of high protein intake on whole-body protein breakdown and muscle protein synthesis rates in these burn patients, although high-protein diets may enhance wound healing.

Mixed Venous Oxygen Saturation During Cardiopulmonary Bypass Poorly Predicts Regional Venous Saturation

Mixed venous oxygen saturation is generally accepted as an indicator of adequacy of systemic oxygen delivery; however, cardiopulmonary bypass (CPB) may alter this relationship.Major postoperative complications potentially secondary to inadequate oxygen delivery during CPB indicate that mixed venous oxygen saturation may not detect regional venous desaturation during CPB. We therefore tested the hypothesis that mixed venous oxygen saturation and pH did not predict regional venous oxygen saturations and pH during 2 h of bypass in a swine model. Six immature swine (27-34 kg) received standard normothermic CPB. Sagittal sinus and portal vein oxygen saturations and blood gases were measured at 30, 60, 90, and 120 min of bypass. Although the venous reservoir oxygen saturation remained unchanged during 2 h of bypass, sagittal sinus saturation and pH decreased significantly (66% +/- 3.3% to 33% +/- 2.2% and 7.38 +/- 0.04 to 7.23 +/- 0.05, respectively). Likewise in the portal vein, oxygen saturation and pH also decreased (82% +/- 2.4% to 59.3% +/- 3.9% and 7.39 +/- 0.03 to 7.27 +/- 0.06, respectively). We conclude that profound regional venous desaturation and progressive regional acidemia may go undetected even when a standard pump flow rate of 100 mL centered dot kg-1 centered dot min-1 is used and mixed venous oxygen saturation is normal. (Anesth Analg 1995;80:466-72)

Hypertonic saline dextran prime reduces increased intracranial pressure during cardiopulmonary bypass in pigs

Children and adults who develop neurologic deficits after cardiac surgery may experience cerebral ischemia during cardiopulmonary bypass. Increased intracranial pressure (ICP) may contribute to cerebral ischemia during bypass. Hypertonic saline dextran (HSD), a hyperosmotic, hyperoncotic resuscitation solution, decreases ICP in trauma resuscitation. We hypothesized that HSD would decrease ICP, reduce brain water, and reduce intravascular fluid requirements during bypass. Twelve swine were divided into two bypass groups: Group 1 (ISO = isotonic) received as prime 1 L of lactated Ringers solution and 500 mL of 6% hydroxyethyl starch. Group 2 (HSD = hypertonic saline/dextran) received as prime 1 L of lactated Ringers solution, 500 mL of 6% hydroxyethyl starch, and 1 mL/kg of 24% hypertonic saline/25% dextran. Normothermic bypass was instituted at 100 mL.kg-1.min-1. ICP increased significantly during bypass with ISO prime but not with HSD. Brain water in the cerebrum did not differ between groups but was reduced in the cerebellum to 75.9% +/- 1.4%. We conclude that HSD prevented any significant increase in ICP during normothermic bypass, and substantially improved fluid balance during bypass. In cardiac surgery patients in whom maintaining decreased ICP and reducing isotonic fluid administration is important, HSD may be a useful addition to the bypass prime solution.

Performance of an intravenous gas exchanger (IVOX) in a venovenous bypass circuit

To analyze quantitatively the performance of the intravenacaval blood gas exchanger (IVOX), we developed a right atrium-pulmonary artery venovenous extracorporeal bypass circuit. Oxygen transfer and carbon dioxide removal were calculated at different blood flow rates, different hemoglobin levels, and during permissive hypercapnia. Oxygen transfer increased linearly with blood flow up to 41 mL/min. Likewise, O2 transfer increased linearly with hemoglobin levels up to 7.5 g/dL, but no further increases were achieved above this level. Carbon dioxide removal increased linearly as flow increased from 1.0 to 3.0 L/min but did not increase further for higher flows. Carbon dioxide removal was 45 mL/min at blood carbon dioxide tension of 42 mm Hg but increased to a maximum of 81 mL/min at a carbon dioxide tension of 90 mm Hg. We conclude that IVOX is a diffusion-limited device dependent on blood flow, hemoglobin content, and the gas pressure gradient across the membrane. Further engineering improvements are needed to improve the gas exchange performance of IVOX.